The long-term goal of the proposed research program is to understand pathways through which the prefrontal cortex exercises central executive functions. Functional studies in humans suggest that the prefrontal cortex exercises inhibitory control on other areas, a process that is essential for attention and selection of relevant information for specific actions. The goal of the proposed studies is to investigate the anatomic basis of excitatory and inhibitory influences exerted by prefrontal cortices, by studying the organization and synaptology of the largely unexplored efferent pathways from prefrontal cortices to superior temporal areas as a model system. The working hypothesis is that functionally distinct lateral and medial prefrontal cortices, which are associated with distinct aspects of memory, exert varied excitatory and inhibitory effects through different patterns of innervation of excitatory neurons and inhibitory interneurons in temporal cortices. This hypothesis will be tested by investigating: a) the topography, and b) laminar termination of prefrontal axons in temporal cortices; c) the synaptic interactions of prefrontal axon terminals with spiny excitatory neurons and with distinct classes of inhibitory interneurons, identified by their expression of the calcium binding proteins parvalbumin and calbindin; and d) the prevalence and synaptic relationships between inhibitory interneurons in temporal areas that may be recruited directly or indirectly by prefrontal pathways. Prefrontal axon terminals in temporal cortices will be labeled with anterograde tracers, combined with double-labeling for parvalbumin or calbindin processed for correlated light and electron microscopic analysis. Information from this study will provide a foundation to understand the role of the prefrontal cortex in central executive functions, and the resulting imbalance in excitatory and inhibitory control in neurologic and psychiatric diseases.